This invention relates generally to polymer particles and methods of making and using the same.
Small (micron- and nano-sized) polymer particles are useful for many applications, including pharmaceutical uses. Polymer microparticles are useful for injectable and implantable devices because they have a long circulation time in the body and are efficient drug, enzyme, and protein carriers (Tom, J. W. et al. (1993), “Applications of Supercritical Fluids in the Controlled Release of Drugs,” in Supercritical Fluid Engineering Science, pp. 238-257). Crosslinked polymer microparticles have material property benefits over linear polymer particles including improved mechanical strength, greater control of transport properties, material property adjustability and dimensional stability. Some applications of crosslinked polymers are listed in Cooper, A. L. and Holmes, A. B. (1998) Proceedings of the 5th Meeting of Supercritical Fluids Materials and Natural Products Processing, pp. 843-848. Polymer microparticles (both linear and crosslinked) have been used in applications such as dental composites, biostructural fillers and controlled release devices. Some applications of synthetic bone composites are listed in Popov, V. K. et al. (1998) Proceedings of the 5th Meeting of Supercritical Fluids Materials and Natural Products Processing, pp. 45-50.
Controlled release devices are useful in many applications, from medical to agricultural purposes. (Langer, R. (1993), Polymer-Controlled Drug Delivery Systems,” Acc. Chem. Res. 26:537-542; U.S. Pat. No. 5,043,280). Controlled release delivery systems for drugs have a wide variety of advantages over conventional forms of drug administration. Some of these advantages include: decreasing or eliminating the oscillating drug concentrations found with multiple drug administrations; allowing the possibility of localized delivery of the drug to a desired part of the body; preserving the efficacy of fragile drugs; reducing the need for patient follow-up care; increasing patient comfort; and improving patient compliance. (Langer, R. (1990), “New Methods of Drug Delivery,” Science 249:1527-1533).
Crosslinked polymeric release devices have the capability to modify the release profile of a drug or other chemical by modifying the structure of the crosslinked polymer network. A crosslinked polymer network can provide diffusion controlled release of a drug or other chemical. The rate of diffusion of the drug or other bioactive material to be released can be influenced by the mesh size of the network, or the distance between crosslinks, which depends upon the extent of crosslinking in the network. In a biodegradable system, the mesh size of the network will increase with time as the network degrades.
Current polymer microparticle manufacturing techniques all suffer from one or more disadvantages. For example, the spray drying technique usually requires evaporation of solvent in hot air. The high temperatures used can degrade sensitive drugs and polymers. In thermal polymerization, monomer is heated to induce polymerization. Again, the high temperatures used can cause degradation (including lowering the activity of biologically active substances).
Emulsion and suspension polymerizations (see, for example, U.S. Pat. No. 5,603,960 (O'Hagan., et al.)) involve combinations of solvents, emulsifiers, and surfactants where dispersed islands of monomer polymerize through chemical reaction in a sea of solvent. These methods often involve operation at high temperatures and thus have the problems discussed above, use large volumes of solutions that are often environmentally unfriendly, and permit only minimal control over particle size and morphology.
A number of different techniques have been developed to form small particles of polymers using the solvent power of supercritical fluids. Supercritical fluids have liquid-like densities, very large compressibilities, viscosities between those of liquids and gases, and diffusion coefficients that are higher than liquids. Due to the high compressibility, the density (and solvent power) of a supercritical fluid can be adjusted between gas- and liquid-like extremes with moderate changes in pressure (Debenedetti, P. G. et al. (1993), “Rapid Expansion of Supercritical Solutions (RESS): Fundamentals and Applications,” Fluid Phase Equilibria 82:311-321).
The Rapid Expansion of Supercritical Solution (RESS) technique has been used to form small particles of poly(L-lactic acid) (Debenedetti, P. G. et al. (1993), “Supercritical Fluids: A New Medium for the Formation of Particles of Biomedical Interest,” Proceed. Intern. Symp. Control Rel. Bioact. Mater. 20:141-142) and particles of poly(DL-lactic acid) with embedded lovastatin (Tom, J. W. et al. (1993), “Applications of Supercritical Fluids in the Controlled Release of Drugs,” in Supercritical Fluid Engineering Science, pp. 238-257). In the RESS technique, particles of polymer may be made when a polymer is dissolved in a supercritical fluid (usually carbon dioxide) followed by rapid expansion of the fluid. This technique is limited in applicability to compounds that are soluble in the supercritical fluid. Since most drugs are not soluble in supercritical fluids and most polymers have very low solubility in supercritical fluids, the RESS process is not broadly applicable for drug encapsulation (McHugh, M. and Krukonis, V. (1994) Supercritical Fluid Extraction, Butterworth-Heinemann).
In the Precipitation by a Compressed Antisolvent (PCA) technique (also known as the Gas Antisolvent technique), a solid of interest is dissolved in a solvent and the resulting solution is sprayed into a compressed antisolvent (see, for example, U.S. Pat. Nos. 5,833,891 and 5,874,029). In this technique, the antisolvent and solvent are soluble, but the solid of interest is not soluble in the antisolvent. The antisolvent is believed to extract the solvent, precipitating particles of the solid of interest (Randolph, T. W. et al. (1993) Biotech. Prog. 9:429-435). Microparticles of insulin have reportedly been formed using this technique (Yeo, S.-D. et al. (1993), “Formation of Microparticulate Protein Powders Using a Supercritical Fluid Antisolvent,” Biotech. Bioeng. 41:341-346) and linear polymer microparticles have been formed using polymer starting materials (Bodmeier, R. et al. (1995), “Polymeric Microspheres Prepared by Spraying into Compressed Carbon Dioxide,” Pharm. Res. 12(8):1211-1217; U.S. Pat. Nos. 5,833,891; 5,874,029).
There is a need for polymer particles with low residual solvent levels, high additive encapsulation efficiencies, and processes of making polymer particles that allow control of particle size and morphology, with low operating temperatures and efficient bulk production capability. Formation of polymer particles with degradable networks, whether by surface or bulk degradation, are also needed for controlled release of drugs, for example. In particular, highly crosslinked polymer networks with degradable chemistries are desired. Preferably, the extent of crosslinking or mesh size of such highly crosslinked polymer networks is controlled to tailor the release profile of the drug or other chemical to be released. In addition, there is a need for a process that produces polymer particles in situ from polymer precursors such as monomers or oligomers.